title: PPM1A is a RelA phosphatase with tumor suppressor-like activity.
abstract: Nuclear factor-κB (NF-κB) signaling contributes to human disease processes, notably inflammatory diseases and cancer. NF-κB has a role in tumorigenesis and tumor growth, as well as promotion of metastases. Mechanisms responsible for abnormal NF-κB activation are not fully elucidated; however, RelA phosphorylation, particularly at serine residues S536 and S276, is critical for RelA function. Kinases that phosphorylate RelA promote oncogenic behaviors, suggesting that phosphatases targeting RelA could have tumor-inhibiting activities; however, few RelA phosphatases have been identified. Here, we identified tumor inhibitory and RelA phosphatase activities of the protein phosphatase 2C (PP2C) phosphatase family member, PPM1A. We show that PPM1A directly dephosphorylated RelA at residues S536 and S276 and selectively inhibited NF-κB transcriptional activity, resulting in decreased expression of monocyte chemotactic protein-1/chemokine (C-C motif) ligand 2 and interleukin-6, cytokines implicated in cancer metastasis. PPM1A depletion enhanced NF-κB-dependent cell invasion, whereas PPM1A expression inhibited invasion. Analyses of human expression data revealed that metastatic prostate cancer deposits had lower PPM1A expression compared with primary tumors without distant metastases. A hematogenous metastasis mouse model revealed that PPM1A expression inhibited bony metastases of prostate cancer cells after vascular injection. In summary, our findings suggest that PPM1A is a RelA phosphatase that regulates NF-κB activity and that PPM1A has tumor suppressor-like activity. Our analyses also suggest that PPM1A inhibits prostate cancer metastases and as neither gene deletions nor inactivating mutations of PPM1A have been described, increasing PPM1A activity in tumors represents a potential therapeutic strategy to inhibit NF-κB signaling or bony metastases in human cancer.
authors.affiliation: Department of Cancer Biology, Vanderbilt University, Nashville, TN, USA.
authors.forename: X
authors.initials: X
authors.lastname: Lu
authors.affiliation: 1] Department of Cancer Biology, Vanderbilt University, Nashville, TN, USA [2] Division of Surgical Sciences, Vanderbilt University, Nashville, TN, USA.
authors.forename: H
authors.initials: H
authors.lastname: An
authors.affiliation: 1] Vanderbilt Prostate Cancer Center, Vanderbilt University, Nashville, TN, USA [2] Department of Urology, Vanderbilt University, Nashville, TN, USA.
authors.forename: R
authors.initials: R
authors.lastname: Jin
authors.affiliation: Division of Otolaryngology, Department of Surgery, Yale University, New Haven, CT, USA.
authors.forename: M
authors.initials: M
authors.lastname: Zou
authors.affiliation: Department of Cancer Biology, Vanderbilt University, Nashville, TN, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Department of Biostatistics, Vanderbilt University, Nashville, TN, USA.
authors.forename: P-F
authors.initials: PF
authors.lastname: Su
authors.affiliation: Division of Otolaryngology, Department of Surgery, Yale University, New Haven, CT, USA.
authors.forename: D
authors.initials: D
authors.lastname: Liu
authors.affiliation: Department of Biostatistics, Vanderbilt University, Nashville, TN, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Shyr
authors.affiliation: 1] Division of Otolaryngology, Department of Surgery, Yale University, New Haven, CT, USA [2] Department of Pathology, Yale University, New Haven, CT, USA [3] Yale Cancer Center, New Haven, CT, USA.
authors.forename: W G
authors.initials: WG
authors.lastname: Yarbrough
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D002467:Cell Nucleus / Q000378:metabolism; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D015870:Gene Expression; D064593:Heterografts; D006801:Humans; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D009362:Neoplasm Metastasis; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D000071636:Protein Phosphatase 2C; D021381:Protein Transport; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: C111835:CCL2 protein, human; D018932:Chemokine CCL2; D016328:NF-kappa B; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D025521:Tumor Suppressor Proteins; C000607456:PPM1A protein, human; C000607457:PPM1B protein, human; C000607460:PPM1G protein, human; D010749:Phosphoprotein Phosphatases; C000607466:Ppm1a protein, mouse; D000071636:Protein Phosphatase 2C